This invention relates to non-nucleoside reverse transcriptase inhibitors active against HIV-1 and having an improved resistance and pharmacokinetic profile. The invention further relates to novel intermediates in the synthesis of such compounds and the use of the compounds in antiviral methods and compositions.
Non nucleoside reverse transcriptase inhibitors (NNRTI) bind to an allosteric site on reverse transcriptase and represent an important development in the arsenal of drugs against HIV, particularly HIV-1. International patent application WO 93/03022, discloses thiourea NNRTI which were later denoted xe2x80x9cPETTxe2x80x9d (phenyl ethyl thiazolyl thiourea) compounds in J Med Chem 39 6 1329-1335 (1995) and J Med Chem 39 21 4261-4274 (1996). International patent application nos. WO99/47501, WO/0039095, WO/0056736, WO00/78315 and WO00/78721 describe thiourea PETT derivatives which have allegedly been optimised against a composite RT binding pocket.
International patent application no WO95/06034 and J Med Chem 42 4150-4160 (1999) disclose urea isosteres of PETT NNRTIs. International patent application no WO99/36406 discloses urea NNRTI compounds with a freestanding cyclopropyl bridge, wherein the phenyl left hand wing bears an obligate 6-hydroxy function and international patent application no WO00/47561 discloses prodrugs of such compounds.
Although the urea and thiourea NNRTI disclosed in the above documents are active against reverse transcriptase, especially that of HIV-1, the nature of the HIV virus with its extreme lack of replicative fidelity and consequent tendency to rapid resistance development prompts a demand for further antiretroviral agents with enhanced antiviral performance against problematic drug escape mutants, notably at the RT 100,103 and/or 181 positions.
Additionally, modern HIV therapy regimes, denoted HAART, Highly Active Anti Retroviral Therapy, administer antivirals as combinations of three or more antivirals of various classes, which combinations are administered for prolonged periods, if not for life. HAART requires the patient to follow a complicated dosing schedule with sometimes dozens of tablets per day taken at various times of the day in some cases before and in other cases after the ingestion of food. There is thus a need for antiretroviral preparations allowing greater flexibility in dosing to facilitate patient compliance.
In accordance with a first aspect of the invention there are provided compounds of the formula I: 
where;
R1 is O, S;
R2 is an optionally substituted, nitrogen-containing heterocycle, wherein the nitrogen is located at the 2 position relative to the (thio)urea bond;
R3 is H, C1-C3 alkyl,
R4-R7 are independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, haloC1-C6 alkyl, C1-C6 alkanoyl, haloC1-C6 alkanoyl, C1-C6 alkoxy, haloC1-C6 alkoxy, C1-C6 alkyloxy-C1-C6 alkyl, haloC1-C6 alkyloxy-C1-C6 alkyl hydroxy-C1-C6 alkyl, amino-C1-C6 alkyl, carboxy-C1-C6 alkyl, cyano-C1-C6 alkyl, amino, carboxy, carbamoyl, cyano, halo, hydroxy, keto and the like;
X is xe2x80x94(CH2)nxe2x80x94Dxe2x80x94(CH2)m 
D is xe2x80x94NR8xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94 or xe2x80x94S(xe2x95x90O)2xe2x80x94
R8 is H, C1-C3 alkyl
n and m are independently 0 or 1;
and pharmaceutically acceptable salts and prodrugs thereof.
The currently preferred value for R1 is 0, that is a urea derivative, although R1 as S (ie a thiourea derivative) is also highly potent.
Representative values for R2 include thiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, indolyl, triazolyl, tetrazolyl, piperidyl, piperazinyl and fused rings such as benzothiazolyl, benzopyridyl, benzodiazolyl, benzimidazolyl, quinolyl, purinyl and the like, any of which can be optionally substituted.
Preferred R2 values include pyrid-2-yl and thiazol-2-yl.
The optional substituents to R2 can include up to three substituents such as C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C8 alkynyl, C2-C8 alkenoxy, C1-C6 alkoxy C1-C6 alkyl, C1-C6 alkanoyl, haloC1-C6 alkyl, C1-C4 alkanoyloxy, C1-C4 alkylthio, amino (including C1-C3 alkyl-substituted amino), carboxy, carbamoyl, cyano, halo, hydroxy, aminomethyl, carboxymethyl, hydroxymethyl, nitro, aryl, (such as phenyl, pyrrol-1-yl, tetrazol-5-yl, triazol-4-yl, pyridyl, pyrimidyl, pyrazinyl, imidazolyl, indolyl, piperidyl, piperazinyl, and the like) substituted (as herein defined) aryl, or xe2x80x94SO2Q or xe2x80x94C(xe2x95x90O)Q, where Q is C1-C6 alkyl, halosubstituted C1-C6 alkyl, aryl (as herein defined), substituted (as herein defined) aryl or amino. Heteroatoms in R2 can be derivatised, such as with C1-C6 alkyl, oxo and the like. The optional R2 substituent may be ortho or meta to the bond to the (thio)urea function but is preferably para.
Preferred optional substituents to R2 include ethynyl, phenoxy, pyrrid-1-yl, cyclopropyl, phenyl, halo-substituted phenyl (especially para and meta chloro and fluorophenyl), and dimethylamino. Particularly preferred R2 substituents include halo (F, Br, Cl and I) and cyano. Preferred halo groups include Cl.
The currently preferred value for R3 is H.
Preferably R4 is hydrogen, halo or hydroxy, especially fluoro.
Preferably R5 is halo, C1-3 alkylcarbonyl, C1-3alkyloxy or H, especially fluoro and most preferably H.
Preferably R6 is hydrogen, halo, C1-C3alkyloxy, C1-3alkylcarbonyl, cyano or ethynyl, especially methoxy or fluoro and most preferably H.
Preferably R7 is hydrogen, halo, C1-3alkyloxy, or C1-3alkylcarbonyl, most preferably fluoro.
Preferably R5 and R6 are H and R4 and R7 are halo, most preferably both are fluoro. Preferably D is xe2x80x94Oxe2x80x94, n is 0, m is 1, R1 is O, R2 is substituted pyrid-2-yl and R3 is H. An alternative preferred embodiment embraces compounds wherein D is xe2x80x94Oxe2x80x94, n is 0, m is 1, R1 is S, R2 is substituted pyrid-2-yl and R3 is H.
The compounds of formula I may be administered as a racemic mixture, but preferably the cyclopropyl moiety intermediate the (thio)urea function, X and the phenyl ring (denoted Y below) is at least 75% such as around 90% enantiomerically pure with respect to the conformation: 
Prefered optical isomers of the compounds of formula I show a negative optical rotation value. Such isomers, for example when X is xe2x80x94Oxe2x80x94CH2xe2x80x94, tend to elute less rapidly from a chiral chromatagram, for example chiral AGP 150xc3x9710 mm, 5 xcexcm; Crom Tech LTD Colomn, flow rate 4 ml/min, mobile phase 89 vol % 10 mM HOAc/NH40Ac in acetonitrile. On the basis of preliminary x-ray crystallography analysis a presently favoured absolute configuration appears to be: 
The currently preferred value for D is xe2x80x94Oxe2x80x94. Convenient values for n and m include 1:0 and 1:1. Preferred values of n:m include 0:2 and especially 0:1, that is a chroman derivative. Particularly preferred compounds have stereochemistry corresponding to (1S. 1aR,7bR)-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl. For the sake of clarity, it is noted that the structure: 
The expression C1-Cn alkyl, where n is 3, 6, 7 etc or lower alkyl includes such groups as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, 3-methyl pentyl and the like. The term halo refers to chloro, bromo, fluoro and iodo, especially fluoro. C1-Cn alkoxy refers to groups such as methoxy, ethoxy, propoxy, t-butoxy and the like. C2-Cn alkenyl, refers to groups such as vinyl, 1-propen-2-yl, 1-buten-4-yl, 1-penten-5-yl, 1-buten-1-yl and the like. C1-Cn alkylthio includes methylthio, ethylthio, t-butylthio and the like. C1-Cn alkanoyloxy includes acetoxy, propionoxy, formyloxy, butyryloxy and the like. C2-Cn alkenoxy includes ethenyloxy, propenyloxy, iso-butoxyethenyl and the like. HaloC1-Cn alkyl (including complex substituents comprising this moiety such as haloC1-Cn alkyloxy) includes alkyls as defined herein substituted 1 to 3 times by a halogen including trifluormethyl, 2-dichloroethyl, 3,3-difluoropropyl and the like. The term amine includes goups such as NH2, NHMe, N(Me)2 which may optionally be substituted with halogen, C1-C7 acyloxy, C1-C6 alkyl, C1-C6 alkoxy, nitro, carboxy, carbamoyl, carbamoyloxy cyano, methylsulphonylamino and the like. Carboxy, carboxymethyl and carbamoyl include the corresponding pharmaceutically acceptable C1-C6 alkyl and aryl esters.
Prodrugs of the compounds of formula I are those compounds which following administration to a patient release a compound of the formula I in vivo. Typical prodrugs are pharmaceutically acceptable ethers and especially esters (including phosphate esters) when any of R4-R7 or the optional substituent to R2 represent an hydroxy function, pharmaceutically acceptable amides or carbamates when any of the R2 substituent or R4-R7 represent an amine function or pharmaceutically acceptable esters when the R2 substituent or R4-R7 represent a carboxy function.
The compounds of formula I can form salts which form an additional aspect of the invention. Appropriate pharmaceutically acceptable salts of the compounds of formula I include salts of organic acids, especially carboxylic acids, including but not limited to acetate, trifluoroacetate, lactate, gluconate, citrate, tartrate, maleate, malate, pantothenate, isethionate, adipate, alginate, aspartate, benzoate, butyrate, digluconate, cyclopentanate, glucoheptanate, glycerophosphate, oxalate, heptanoate, hexanoate, fumarate, nicotinate, palmoate, pectinate, 3-phenylpropionate, picrate, pivalate, proprionate, tartrate, lactobionate, pivolate, camphorate, undecanoate and succinate, organic sulphonic acids such as methanesulphonate, ethanesulphonate, 2-hydroxyethane sulphonate, camphorsulphonate, 2-napthalenesulphonate, benzenesulphonate, p-chlorobenzenesulphonate and p-toluenesulphonate; and inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, hemisulphate, thiocyanate, persulphate, phosphoric and sulphonic acids.
Hydroxy protecting group as used herein refers to a substituent which protects hydroxyl groups against undesirable reactions during synthetic procedures such as those O-protecting groups disclosed in Greene, xe2x80x9cProtective Groups In Organic Synthesis,xe2x80x9d (John Wiley and Sons, New York (1981)). Hydroxy protecting groups comprise substituted methyl ethers, for example, methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, t-butyl and other lower alkyl ethers, such as isopropyl, ethyl and especially methyl, benzyl and triphenylmethyl; tetrahydropyranyl ethers; substituted ethyl ethers, for example, 2,2,2-trichloroethyl; silyl ethers, for example, trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl; and esters prepared by reacting the hydroxyl group with a carboxylic acid, for example, acetate, propionate, benzoate and the like.
The invention further provides pharmaceutical compositions comprising the compounds of the invention and pharmaceutically acceptable carriers or diluents therefor. Additional aspects of the invention provide methods for the inhibition of HIV comprising administering a compound of the formula I to a subject afflicted with or exposed to HIV-1. The HIV-1 may comprise a drug escape mutant, such as HIV strain comprising the mutations at the 100, 103 and/or 181 mutations, especially K103N.
The invention also extends to the use of the compounds of formula I in therapy, such as in the preparation of a medicament for the treatment of HIV infections.
In treating conditions caused by HIV, the compounds of formula I are preferably administered in an amount to achieve a plasma level of around 100 to 5000 nM, such as 300 to 2000 nM. This corresponds to a dosage rate, depending on the bioavailability of the formulation, of the order 0.01 to 10 mg/kg/day, preferably 0.1 to 2 mg/kg/day. A typical dosage rate for a normal adult will be around 0.05 to 5 g per day, preferably 0.1 to 2 g such as 500-750 mg, in one to four dosage units per day. As with all pharmaceuticals, dosage rates will vary with the size and metabolic condition of the patient as well as the severity of the infection and may need to be adjusted for concomitant medications.
In keeping with the usual practice with HIV inhibitors it is advantageous to co-administer one to three additional antivirals to provide synergistic responses and to ensure complementary resistance patterns. Such additional antivirals may include AZT, ddl, ddC, D4T, 3TC, DAPD, alovudine, abacavir, adefovir, adefovir dipivoxil, bis-POC-PMPA, GW420 867X, foscarnet, hydroxyurea, Hoechst-Bayer HBY 097, efavirenz, trovirdine, capravirine, nevirapine, delaviridine, tipranavir, emtricitabine, PFA, H2G (omaciclovir), MIV-606 (valomaciclovir stearate), TMC-126, TMC-125, TMC-120, efavirenz, DMP-450, loviride, ritonavir, (including kaletra), lopinavir, saquinavir, lasinavir, indinavir, amprenavir, amprenavir phosphate, nelfinavir and the like, typically at molar ratios reflecting their respective activities and bioavailabilities. Generally such ratio will be of the order of 25:1 to 1:25, relative to the compound of formula I, but may be lower, for instance in the case of cytochrome antagonists such as ritonavir.
Compounds of the invention are typically prepared as follows: 
(a) DPPA, Et3N, toluene; (b) substituted 2-aminopyridine; (c) aqueous HCl, dioxane; (d) substituted 2-pyridyl isothiocyanate.
Compounds of the general formula (I), wherein R1 is O (urea) or S (thiourea), R2 is, for instance, a 5-substituted pyrid-2-yl, and R3 is H, are prepared by methods shown in Scheme 1. The cyclopropanecarboxylic acid 1-Scheme-1 is converted to the acyl azide and heated to 120xc2x0 C. to induce Curtius rearrangement and provide the isocyanate 2-Scheme-1. The urea 3-Scheme-1 is obtained by coupling of the isocyanate with the relevantly substituted 2-aminopyridine. Hydrolysis of the isocyanate as in step (c) which results in the cyclopropylamine 4-Scheme-1, followed by reaction with a 2-pyridyl isothiocyanate provides the thiourea 5-Scheme-1. The isothiocyanate may be prepared from the optionally ring substituted 2-aminopyridine by known methods, such as treatment with thiophosgene or thiocarbonyldiimidazole. R3 variants of formula I are prepared correspondingly using the appropriately amine-substituted amino-R2, ie 2-(N-methylamino)pyridine for R3 as methyl. Many 2-aminopyridines are commercially available and others are described in literature, for example those shown in Scheme 2. R1xe2x95x90S compounds can alternatively be prepared from the isothiocyanate corresponding to 2-Scheme 2 or from amine 3-Scheme 2 and amino-R2 in conjunction with an RC(xe2x95x90S)Rxe2x80x2 both as described in WO 9303022. Although Scheme 1 has been illustrated with a substituted pyridyl it is readily apparent that corresponding couplings can be used for other R2 variants such as optionally substituted thiazolyl, pyrazinyl, benzothiazolyl, pyrimidinyl etc. 
(a) phenol, NaH, DMF; (b) 10% Pd/C, H2 1 atm, EtOH; (c) PdCl2(PPh3)2, trimethylsilylacetylene, Cul, diisopropylamine; (d) tert-butylammonium fluoride
Replacement of the bromine in 5-bromo-2-nitropyridine by a phenoxy group, followed by reduction of the nitro group affords the 2-amino-5-phenoxypyridine. The Sonogashira coupling of 2-amino-5-iodopyridine with the terminal alkyne SiMe3Cxe2x95x90CH in the presence of catalytic amounts of bis(triphenylphosphine)palladium dichloride and cuprous iodide as in step (c) provides the 2-amino-5-(2-trimethylsilylethynyl)pyridine. Removal of the silyl group by TBAF yields 2-amino-5-ethynylpyridine which can be coupled to the isocyanate as described in Scheme 1. Alternatively, treatment with TBAF may be performed on the urea 3-Scheme-1 or thiourea 5-Scheme-1 where R10 is xe2x80x94Cxe2x89xa1CSiMe3 to convert R10 to xe2x80x94Cxe2x89xa1CH. 
(a) ethyl diazoacetate, catalyst, CH2Cl2; (b) chromatography and then reflux with LiOH, H2O, MeOH; (c) reflux with LiOH, H2O, MeOH and then chromatography; (d) rt, NaOH, H2O, MeOH and then reflux with LiOH, H2O, MeOH
Compounds of the general formula (I), wherein R1 is O (urea) or S (thiourea), R2 is, for example, a 5-substituted pyrid-2-yl, R3 is H, X is xe2x80x94Dxe2x80x94CH2, and wherein the cyclopropyl moiety has the relative configuration 
are prepared by methods shown in Scheme 3. Cyclopropanation of the double bond in the chromene 1-Scheme-3 with ethyl diazoacetate is catalyzed by cuprous or rhodium(II) salts such as Cul, (CuOTf)2-benzene, and Rh2(OAc)4 in solvents such as dichloromethane, 1,2-dichloroethane, or chloroform. The reaction provides a diastereomeric mixture of the cyclopropanecarboxylic acid ethyl esters 2-Scheme-3, with the all cis relative configuration, and its trans isomer 3-Scheme-3. Separation by column chromatography of the cis and trans diastereomers may be accomplished at this stage, followed by hydrolysis of the isolated 2-Scheme-3, such as by refluxing in aqueous methanolic LiOH, to yield a racemic mixture of the all cis cyclopropanecarboxylic acid 4-Scheme-3, as described in step (b). Alternatively, the diastereomeric mixture of ethyl esters may be subjected to hydrolysis, and separation conducted on the mixture of cyclopropanecarboxylic acids to provide the isolated all cis isomer, as in step (c). Step (d) involves isolation of the cis ethyl ester 2-Scheme-3 which may also be done by selective hydrolysis of the trans 3-Scheme-3 at lower temperatures, such as treatment with aqueous methanolic NaOH at ambient temperature. The isolated cis ethyl ester may then be hydrolyzed in the usual manner to the cyclopropanecarboxylic acid 4-Scheme-3. The cyclopropanecarboxylic acid is subjected to the methods outlined in Scheme 1 to obtain the urea or thiourea 5-Scheme-3. The chromenes 1-Scheme-3 are prepared by methods shown in Schemes 4, 5, and 6.
Although this scheme 3 has been illustrated with a Dxe2x95x90O variant it will be apparent that corresponding manipulations will be available to the Dxe2x95x90S, Sxe2x95x90O; S(xe2x95x90O)2 and Dxe2x95x90NR8 variants. When R8 is H, the nitrogen is typically protected with a conventional secondary amine protecting group, such as those described in Greene and Wuts Protective Groups in Organic Synthesis 2nd ed, Wiley NY 1991). 
(a) 3-bromopropyne, K2CO3, acetone; (b) N,N-diethylaniline or PEG-200, 225xc2x0 C.
Scheme 4 describes the preparation of chromenes, including many from commercially available disubstituted phenols, such as those wherein the substitution pattern in the benzene ring is as follows: R4 and R7 are halo; R4 and R6 are halo; R5 and R7 are halo; R4 is halo and R7 is C1-3 alkylcarbonyl; and R4 is hydroxy while R5 is C1-3 alkylcarbonyl. Reaction of the available disubstituted phenol 1-Scheme-4 with 3-bromopropyne in the presence of a base, such as K2CO3 in acetone or NaH in DMF, results in nucleophilic substitution of the halide to provide the ether 2-Scheme-4. Ring closure may be accomplished by heating the ether in N,N-dimethylaniline or polyethylene glycol to yield the chromene 3-Scheme-4. 
NaBH4, EtOH; (b) p-toluenesulfonic acid, toluene, reflux;
Scheme 5 describes the preparation of chromenes, used as starting material in Scheme 3, from the appropriately substituted chromanones, which are readily accessed from commercially available chromanones, for example those wherein one of the positions in R4 to R7 is substituted with halo or C1-3 alkoxy. Conversion of the carbonyl group in 4-chromanone 1 a-Scheme-5 and to the correponding alcohol by a suitable reducing agent such sodium borohydride in ethanol provides 2-Scheme-5. Refluxing the alcohol with small amounts of acid, such as p-TsOH in toluene, causes dehydration of 2-Scheme-5 to the desired chromene 1-Scheme-3. Corresponding manipulations will be available for other D variants. For example the corresponding 2H-1-benzothiopyran is readily prepared from commercially available (substituted) thiochroman-4-ones by reaction with a reductant such as a metal hydride for example lithium aluminium hydride in an organic solvent such as ether, followed by dehydration such as refluxing with an acid for example potassium acid sulphate or the like. 
(a) allyl bromide, K2CO3, acetone; (b) Ph3PCH3Br, NaH, THF; (c) C12[Pcy3]2Ruxe2x95x90CHPh, CH2Cl2 (d) Ph3P+CHxe2x95x90CH2 Brxe2x88x92, DBU
Chromenes, for use as starting material in Scheme 3, are prepared from substituted o-hydroxybenzaldehydes as shown by methods outlined in Scheme 6. Reaction of 1-Scheme-6 with allyl bromide in the presence of a base, such as K2CO3 in acetone, results in nucleophilic substitution of the halide to provide the ether 2-Scheme-6. Witting reaction transforms the aldehydic group into the olefin and provides 3-Scheme-6. The pair of terminal double bonds may undergo metathesis intramolecularly by treatment with a catalyst such as the ruthenium complex Grubb""s catalyst in step (c) to produce the chromene. Alternatively 1-Scheme-6 can be cyclised directly as shown in step d) in the legend above. 
(a) Pd(0), DPPP, Et3N, (CH3)3SiCxe2x95x90CH; (b) Pd(0), butyl vinyl ether, DMF; (c) Pd(0), Zn(CN)2, DMF; (d) NaOH, H2O, MeOH
Pd(0) catalyzed coupling of the triflate 1-Scheme-7 leads to the replacement of the trifluoromethanesulfonyloxy group and the introduction of other substiutents at R6. Thus, Scheme 7 provides the preparation of synthesis intermediates for use in scheme 3 to give the urea or thiourea 5-Scheme-3 wherein R6 is cyano, ethynyl, or C1-3 alkylcarbonyl. 
Convenient routes to compounds wherein X is xe2x80x94CH2xe2x80x94Oxe2x80x94 are depicted in Scheme 8, where Ra and Rb are optional substituents R4-R7, which are suitably protected with conventional protecting groups as necessary and Rc is a lower alkyl ester. Optionally substituted phenol 1-Scheme-8 which is hydroxy-protected with a protecting group such as methyl, MOM and the like is reacted with a base such as BuLi or the like in a solvent such as THF or the like and transformed to zinc salt by adding zinc chloride or the like. A catalyst such as Pd(OAc)2 or the like is added along with an activated acrylate such as lower alkyl-cis-3-haloacrylate, for example BrCHxe2x95x90CHCOOEt or the like. The reaction mixture is cooled and a reducing agent such as DIBAL or the like is added portionwise and quenched to yield 2-Scheme-8. A hydrazone such as the p-toluenesulfonylhydrazone of glyoxylic acid chloride or the like and a base such as N,N-dimethylaniline or the like is added in a solvent such as CH2Cl2 or the like followed by the addition of another base such as Et3N or the like to yield 3-Scheme-8. The reaction product is dissolved in a solvent such as dichloromethane or the like which is preferably degassed. A chiral Doyle""s catalyst such as Rh2(5-R-MEPy)4 (U.S. Pat. No. 5,175,311, available from Aldrich or Johnson Matthey), or the like is added to yield 4-Scheme-8 in a high enantiomeric excess such as greater than 80, preferably greater than 90% ee. Preferably, this compound is first reacted with BBr3 in dichloromethane followed by the addition of acetonitrile the reaction mixture and finally sodiumhydroxide is added to give 6-Scheme-8. Alternatively, this product (4-Scheme-8) is ring-opened with an electrophile preferably HBr or the like under in conjunction with an acid such as AcOH or the like. Under acid conditions a spontaneous ring closure takes place to form chromenone 5-Scheme-8. When subjected to basic conditions such as NaOH or the like, the chromenone rearranges to form the chromencyclopropylcarboxylic acid 6-Scheme-8. Alternatively, 4-Scheme-8, for instance when the phenolic protecting group is MOM, can be subjected to basic conditions such as NaOH, carbon dioxide and a lower alkyl halide such as iPrl in a solvent such as DMSO to open the lactone and yield the alkyl ester 7-Scheme-8. Displacement of the hydroxy protecting group and ring closure with the free hydroxymethyl moiety occurs in acidic conditions such as iPrOH/HCl or the like followed by DEAD; PPH3 in an organic solvent such as THF or the like. Alternatively, in a convergent approach, compound 1-Scheme-8 is reacted with BuLi and transformed to a zinc salt. This salt reacted with the cyclopropyliodide, 9-Scheme-8, in a palladium-catalyzed reaction to give after reaction with Jone""s reagent compound 4-Scheme-8. This carboxylic acid is in turn converted to the isocyanate as shown in Scheme 1 and subsequently to the heteroarylurea or heteroarylthiourea of the Formula I.
A further aspect of the invention provides novel intermediates useful in the above described syntheses of the compound of formula I. A preferred group of intermediates include compounds of the formula II: 
where X and R4-R7 are as defined above and R11 is xe2x80x94C(O)OR12, where R12 is H or a carboxy protecting group such as a lower alkyl ester; xe2x80x94NCO, xe2x80x94NCS or an amine such as NH2. A favoured subset of the compounds of formula II have the formula III: 
where R4 and R7 are independently halo, most preferably fluoro, and R11 is xe2x80x94COOH, a lower alkyl ester thereof, isocyanate, isothiocyanate or amino.
A further group of preferred intermediates includes compounds of the formula IV 
where R4 to R7 are as defined above, PG is an hydroxy protecting group and PG* is an hydroxy protecting group or together with the adjacent O defines a keto function.
A preferred subset of compounds of formula IV are those of formula V: 
where R4 and R7 are independently halo, most preferably fluoro, PG is lower alkyl, such as isopropyl, ethyl and most preferably methyl and PG* is lower alkyl such as isopropyl, ethyl and most preferably methyl or together with the adjacent O defines a keto group
A still further group of preferred intermediates includes compounds of the formula VI: 
where R4-R7 are as defined above, PG is an hydroxy protecting group and R13 is H, an ester thereof or an hydroxy protecting group. A preferred subset within formula VI has the formula VII: 
where R4 and R7 are independently halo, preferably fluoro, PG is lower alkyl, such as isopropyl, ethyl and most preferably methyl and R12 is H or xe2x80x94C(xe2x95x90O)CHxe2x95x90Nxe2x95x90N.
Favoured compounds of formula I include
cis-1-(5-Cyano-pyridin-2-yl)-3-(1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-yl)-urea,
cis-1-(5-Cyano-pyridin-2-yl)-3-(1,1a,3,7b-tetrahydro-2-oxa-cyclopropa[a]naphthalen-1-yl)-urea,
cis-1-(5-Cyano-pyridin-2-yl)-3-(7-hydroxy-6-propionyl-1, 1 a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-urea,
cis-1-(6-Acetyl-7-hydroxy-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-3-(5-cyano-pyridin-2-yl)-urea,
cis-1-(5-Cyanopyridin-2-yl)-3-(7-fluoro-4-propionyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-urea,
cis-1-(5-Cyano-pyridin-2-yl)-3-(7-fluoro-4-methoxy-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-urea,
cis-1-(5-Cyano-pyridin-2-yl)-3-(7-fluoro-4-chloro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-urea,
cis-1-(5-Chloro-pyridin-2-yl)-3-(4-chloro-7-fluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-yl)-urea,
cis-1-(5-Bromo-pyridin-2-yl)-3-(4-chloro-7-fluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-yl)-urea,
cis-1-(5-Cyano-pyridin-2-yl)-3-(5-cyano-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-urea,
cis-1-(5-Cyano-pyridin-2-yl)-3-(5-ethynyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-urea,
cis-1-(5-Acetyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-3-(5-cyano-pyridin-2-yl)-urea,
cis-1-(5-Methoxy-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-3-(5-cyano-pyridin-2-yl)-urea,
cis-1-(5-Cyano-pyridin-2-yl)-3-(N-acetyl-1,1a,3,7b-tetrahydro-2-oxa-cyclopropa[a]quinoline-1-yl))-urea,
cis-1-(5-Cyano-3-methyl-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-urea,
cis-1-(4,7-Difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-3-(5-ethynyl-pyridin-2-yl)-urea,
cis-1-(5-Bromo-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-urea,
cis-1-(4,7-Difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-3-(5-phenoxy-pyridin-2-yl)-urea,
cis-1-(5-Cyano-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-thiourea,
1-(6-Chloro-5-cyano-pyridin-2-yl)-3-(5,7-difluoro-1, 1 a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)urea,
1-(5-Cyano-pyridin-2-yl)-3-(5,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)urea,
cis-1-(4-Bromo-7-fluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-3-(5-cyano-pyridin-2-yl)-urea,
cis-1-(4-Bromo-7-fluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-3-(6-chloro-5-cyano-pyridin-2-yl)-urea,
cis-1-(4-Bromo-6-fluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-3-(5-cyano-pyridin-2-yl)-urea,
cis-1-(4-Bromo-6-fluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-3-(6-cloro-5-cyano-pyridin-2-yl)-urea,
cis-1-(5-Cyanopyridin-2-yl)-3-(6-fluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)urea,
cis N-[1a, 6b-dihydro-1H-benzo[b]cyclopropa[d]thien-1-yl]-Nxe2x80x2-(5-cyano-2-pyridinyl)-urea,
N-[(1S,1aR,7bR) or (1R,1aS,7bS)-1.1a,2,7b-tetrahydrocyclopropa[c]-[1 ]benzothiopyran-1-yl]-Nxe2x80x2-(5-cyano-2-pyridinyl) urea,
cis-N-(5-bromo-2-pyridinyl)-Nxe2x80x2-(7-chloro-4-fluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl)urea,
cis-N-(7-chloro-4-fluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl)-Nxe2x80x2-(5-chloro-2-pyridinyl)urea,
cis-N-(7-chloro-4-fluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl)-Nxe2x80x2-(5-cyano-2-pyridinyl)urea,
cis-N-(5-phenoxy-2-pyridinyl)-Nxe2x80x2-(4,7-dichloro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl)urea,
cis-N-(5-bromo-2-pyridinyl)-Nxe2x80x2-(4,7-dichloro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl)urea,
cis-N-(5-chloro-2-pyridinyl)-Nxe2x80x2-(4,7-dichloro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl)urea,
cis-N-(5-cyano-2-pyridinyl)-N-(4,7-dichloro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl)urea,
N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-Nxe2x80x2-(5-fluoro-2-pyridinyl)urea,
N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-Nxe2x80x2-(5-iodo-2-pyridinyl)urea,
N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-Nxe2x80x2-(3-isoxazolyl)urea,
N-[(1S,1 aR,7bR)-4,7-difluoro-1,1 a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-Nxe2x80x2-[4-(4-chlorophenyl)-1,3-thiazol-2-yl]urea,
N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-Nxe2x80x2-(6-fluoro-1,3-benzothiazol-2-yl)urea,
N-[(1S,1 aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-Nxe2x80x2-(4-pyrimidinyl)urea
N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N-(2-pyrazinyl)urea,
N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-Nxe2x80x2-(5-cyclopropyl-1H-pyrazol-3-yl)urea
and pharmaceutically acceptable salts thereof, especially enantiomerically enriched, for example greater than 80% by weight, preferably  greater than 90%, such as  greater than 97% ee or pure preparations comprising the (xe2x88x92) enantiomer.
Particularly preferred compound thus include
(xe2x88x92)-cis-1-(5-Cyano-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-urea,
(xe2x88x92)cis-1-(5-Chloro-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-urea; or
(xe2x88x92)-cis-1-(5-Cyano-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-thiourea;
(xe2x88x92)-cis-1-(5-Fluoropyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-urea,
(xe2x88x92)-cis-1-(5-Fluoropyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-thiourea;
and pharmaceutically acceptable salts thereof.
While it is possible for the active agent to be administered alone, it is preferable to present it as part of a pharmaceutical formulation. Such a formulation will comprise the above defined active agent together with one or more acceptable carriers or excipients and optionally other therapeutic ingredients. The carrier(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient.
The formulations include those suitable for rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration, but preferably the formulation is an orally administered formulation. The formulations may conveniently be presented in unit dosage form, e.g. tablets and sustained release capsules, and may be prepared by any methods well known in the art of pharmacy.
Such methods include the step of bringing into association the above defined active agent with the carrier. In general, the formulations are prepared by uniformly and intimately bringing into association the active agent with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product. The invention extends to methods for preparing a pharmaceutical composition comprising bringing a compound of Formula I or its pharmaceutically acceptable salt in conjunction or association with a pharmaceutically acceptable carrier or vehicle. If the manufacture of pharmaceutical formulations involves intimate mixing of pharmaceutical excipients and the active ingredient in salt form, then it is often preferred to use excipients which are non-basic in nature, i.e. either acidic or neutral. Formulations for oral administration in the present invention may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active agent; as a powder or granules; as a solution or a suspension of the active agent in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water in oil liquid emulsion and as a bolus etc.
With regard to compositions for oral administration (e.g. tablets and capsules), the term suitable carrier includes vehicles such as common excipients e.g. binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, polyinylpyrrolidone (Povidone), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sucrose and starch; fillers and carriers, for example corn starch, gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride and alginic acid; and lubricants such as magnesium stearate, sodium stearate and other metallic stearates, stearic acid, glycerol stearate, silicone fluid, talc waxes, oils and colloidal silica. Flavouring agents such as peppermint, oil of wintergreen, cherry flavouring or the like can also be used. It may be desirable to add a colouring agent to make the dosage form readily identifiable. Tablets may also be coated by methods well known in the art. A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active agent in a free flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may be optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active agent.
Other formulations suitable for oral administration include lozenges comprising the active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active agent in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active agent in a suitable liquid carrier.
Various aspects of the invention will now be illustrated by way of example only with reference to the following non-limiting examples.